Promiscuous G-protein activation by the calcium-sensing receptor

• 成果类型: Article
• 署名作者: Zuo, Hao; Park, Jinseo; Frangaj, Aurel; Ye, Jianxiang; Lu, Guanqi; Manning, Jamie J.; Asher, Wesley B.; Lu, Zhengyuan; Hu, Guo-bin; Wang, Liguo; Mendez, Joshua; Eng, Edward; Zhang, Zhening; Lin, Xin; Grassucci, Robert; Hendrickson, Wayne A.; Clarke, Oliver B.; Javitch, Jonathan A.; Conigrave, Arthur D.; Fan, Qing R.
• 署名单位: Columbia University; Columbia University; Columbia University; Columbia University; New York State Psychiatry Institute; United States Department of Energy (DOE); Brookhaven National Laboratory; Columbia University; Columbia University; Columbia University; University of Sydney; Columbia University
• 刊物名称: Nature
• ISSN/ISSBN: 0028-6850
• DOI: 10.1038/s41586-024-07331-1
• 发表日期: 2024-05-09
• 页码: 481-+
• 关键词: cryo-em structure; ca2+-sensing receptor; membrane-proteins; amino-acids; cell; expression; secretion; Visualization; mutations; terminus

摘要

The human calcium-sensing receptor (CaSR) detects fluctuations in the extracellular Ca2+ concentration and maintains Ca2+ homeostasis(1,2). It also mediates diverse cellular processes not associated with Ca2+ balance(3-5). The functional pleiotropy of CaSR arises in part from its ability to signal through several G-protein subtypes(6). We determined structures of CaSR in complex with G proteins from three different subfamilies: G(q), G(i) and G(s). We found that the homodimeric CaSR of each complex couples to a single G protein through a common mode. This involves the C-terminal helix of each G alpha subunit binding to a shallow pocket that is formed in one CaSR subunit by all three intracellular loops (ICL1-ICL3), an extended transmembrane helix 3 and an ordered C-terminal region. G-protein binding expands the transmembrane dimer interface, which is further stabilized by phospholipid. The restraint imposed by the receptor dimer, in combination with ICL2, enables G-protein activation by facilitating conformational transition of G alpha. We identified a single G alpha residue that determines G(q) and G(s) versus G(i) selectivity. The length and flexibility of ICL2 allows CaSR to bind all three G alpha subtypes, thereby conferring capacity for promiscuous G-protein coupling. Structures of the human calcium-sensing receptor can be bound into complex with G proteins from three different G alpha subtypes while maintaining G-protein-binding specificity.